Process for preparing 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone

ABSTRACT

A five-step process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]-ethanone of the formula  
                 
 
     starting from 4-(methylthio)benzyl alcohol is described.  
     The compound of the formula I is an intermediate for preparing COX-2 inhibitors, pharmaceutically active compounds having analgesic and antiinflammatory action.

DESCRIPTION

[0001] The invention encompasses a novel process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone of the formula

[0002] 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone is an important intermediate for preparing so-called COX-2 inhibitor, pharmaceutically active compounds having analgesic and antiinflammatory action (R. S. Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998) 2777-2782; WO 98/03484).

[0003] The object of the invention was to provide a technically feasible process for preparing the intermediate of the formula I.

[0004] This object was achieved by the novel process according to claim 1.

[0005] The process according to the invention is characterized by five steps, where,

[0006] in the first step a), 4-(methylthiobenzyl alcohol is converted with hydrochloric acid into 4-(methylthio)benzyl chloride,

[0007] in the second step b), 4-(methylthio)benzyl chloride is converted with an alkali metal cyanide into 4-(methylthio)phenylacetonitrile,

[0008] in the third step c), 4-(methylthio)phenylacetonitrile is condensed with a 6-methylnicotinic ester to give 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine of the formula

[0009] in the fourth step d), 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine is hydrolysed and decarboxylated under acidic conditions to give 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine of the formula

[0010] and, in the last step e), 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine is oxidized to give the end product.

[0011] Step a:

[0012] The chlorination of 1-(methylthio)benzyl alcohol to 4-(methylthio)benzyl chloride is carried out using hydrochloric acid, advantageously using concentrated hydrochloric acid, at a temperature of from 10° C. to 40° C. The reaction is usually carried out in an organic solvent, advantageously in a water-immiscible solvent, such as, for example, in toluene.

[0013] Typically, the chlorination takes about 1 h to 4 h. The 4-(methylthio)benzyl chloride can be obtained in a simple manner by neutralizing the organic phase and removing the solvent. Further purification can be achieved by distillation.

[0014] Step b:

[0015] The cyanidation of 4-(methylthio)benzyl chloride is carried out using an alkali metal cyanide, advantageously in the presence of a phase transfer catalyst.

[0016] Suitable alkali metal cyanides are sodium cyanide or potassium cyanide.

[0017] The phase transfer catalysts which can be chosen are known in the art. Suitable are tetraalkylammonium halides, such as, for example, tetra-n-butylammonium chloride or tetra-n-butylammonium bromide.

[0018] In general, the reaction is carried out in the presence of a water-immiscible solvent, such as, for example, toluene; if appropriate, water can be added.

[0019] The reaction temperature is advantageously from 60° C. to 100° C.

[0020] After a reaction time of 1 h to 6 h, the product can be isolated in a simple manner from the organic phase by removing the solvent.

[0021] Further purification of the product can be achieved by recrystallization from, for example, diisopropyl ether.

[0022] Step c:

[0023] In the third step, ((methylthio)phenyl)acetonitrile is condensed with a 6-methylnicotinic ester to give 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl]-(6-methyl)pyridine of the formula

[0024] The condensation is advantageously carried out in the presence of an alkali metal alkoxide, at a temperature between 60° C. and 110° C.

[0025] Suitable alkali metal alkoxides are, for example, sodium methoxide or potassium tert-butoxide. The reaction is advantageously carried out in the presence of a lower alcohol or an aromatic hydrocarbon as solvent.

[0026] After the condensation, the 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine can be obtained, for example, by adding the reaction mixture to cold water and precipitating the product from the aqueous phase by acidifying it slightly.

[0027] Step d:

[0028] Hydrolysis and decarboxylation to give 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine of the formula

[0029] are carried out under acidic conditions.

[0030] Suitable acids are hydrochloric acid, phosphoric acid or mixtures of acetic acid with a mineral acid. Advantageously, a mixture of acetic acid and a mineral acid is employed, at a temperature of from 50° C. to 115° C.

[0031] Particular preference is given to mixtures of acetic acid with concentrated hydrochloric acid or mixtures of acetic acid with concentrated sulphuric acid. If appropriate, a certain amount of water can be added to the mixtures.

[0032] Good results were obtained using mixtures of acetic acid/concentrated hydrochloric acid 1:3 or acetic acid/concentrated sulphuric acid/water 1:1:1.

[0033] After a reaction time of about 1 h to 20 h, the mixture can be neutralized using, for example, an aqueous ammonia solution, as a result of which the product precipitates out and can be isolated in a simple manner.

[0034] Step e:

[0035] Oxidation of 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine to the end product is advantageously carried out using hydrogen peroxide in the presence of an alkali metal tungstate, at a temperature of from 10° C. to 40° C., preferably at about 20° C.

[0036] A particularly suitable alkali metal tungstate is sodium tungstate of the formula Na WO₁.2H⁻O. The alkali metal tungstate is generally employed in catalytic amounts of from 0.5 mol % to 20 mol %, based on the 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine used. The reaction is advantageously carried out in the presence of a lower alcohol as solvent. After a reaction time of about 1 h to 6 h, the end product can be precipitated out by addition of water and then be isolated without any problems.

EXAMPLES

[0037] Preparation of 4-(methylthio)benzyl chloride

[0038] Under an atmosphere of nitrogen, 78.7 g (500 mmo)l [sic] of 4-(methylthio)benzyl alcohol were dissolved in 154.5 g of toluene. 131.6 g, (1.3 mol) of conc. HCl were added, and the mixture was stirred at 20-25° C. for 30 min. After 2 h (no starting material left according to TLC), the reaction mixture was diluted with 349 g of toluene and the aqueous phase was separated off. The organic phase was neutralized using 14.0 g of NaHCO and, after 15 min, filtered, and the solvent was evaporated. The residue that remained consisted of 107.4 g of a yellow oil with toluene, corresponding to a yield of >95% (according to NMR). ¹H-NMR (CDCl₃): 7.30 (2H, d); 7.22 (2H, d); 4.55 (2H, s); 2.47 (3H, s). ¹H-NMR (DMSO): 7.37 (2H, d); 7.25 (2H, d); 4.73 (2H, d); 2.47 (3H, s).

[0039] Preparation of 4-(methylthio)phenylacetonitrile

[0040] Under an atmosphere of nitrogen, 25.9 g (150 mmol) of 4-(methylthio)benzyl chloride were dissolved in 45.5 g of toluene. 9.29 (180 mmol) of sodium cyanide, 0.92 g (2.9 mmol) of tetrabutylammmonium chloride and 14.4 g of water were then added. The mixture was stirred at 80-85° C. for 2 h. The reaction mixture was admixed with 30 g of toluene and 45 g of water, the aqueous phase was decanted off and the organic phase was concentrated. This gave a residue of 24.6 g of the title product in a yield of >95 (according to NMR) in the form of a pink solid. H-NMR (CDCl₃): 7.25 (4H, m); 3.70 (2H, s); 2.47 (3H, s).

[0041] Preparation of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine

[0042] Under an atmosphere of nitrogen, a mixture of 38.5 g (250 mmol) of ethyl 6-methylnicotinate, 29.9 g (500 mmol) of sodium methoxide (90.5 ) and 300 ml of toluene was added, at 85-90° C. and over the course of 30 min, to a solution of 47.3 g (250 mmol) of 4-(methylthio)phenylacetonitrile in 75 ml of toluene. This mixture was stirred under reflux for 14 h, then distilled until the overhead temperature exceeded 110° C. and kept at reflux for another 6 h. The reaction mixture was poured into 500 g of ice water, the organic phase was decanted off and the aqueous phase was extracted with 3×100 ml of toluene. The aqueous phase was acidified to pH 6.0 using conc. HCl. The resulting yellow-beige suspension was filtered and the residue was washed with water and dried. This gave 53.9 g (76%) of the title product in the form of a yellow solid. ¹H-NMR (CDCl₃): 9.00 (1H, s); 8.10 (1H, d);  7.3 (5H, m), 5.45 (1H, s); 2.60 (3H, s); 2.45 (3H, s).

[0043] Preparation of 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine

[0044] A mixture of 8.0 g (28 mmol) of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine, 20 ml of acetic acid and 60 ml of concentrated hydrochloric acid was heated at 95° to 100° C. for 1.5 h.

[0045] The orange solution was cooled and adjusted to pH 10 using concentrated ammonia solution. The resulting yellow-beige suspension was filtered and the residue was washed with water and dried. This gave 5.35 g (74°) of the title product in the form of a yellow solid. ¹H-NMR (CDCl₃): 9.10 (1H, s); 8.15 (1H, d);  7.2 (5H, m); 4.21 (2H, s); 2.61 (3H, s); 2.45 (3H, s).

[0046] Preparation of 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone

[0047] Under an atmosphere of nitrogen, a suspension of 8.9 g (34.5 mmol) of 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine in 90 ml of methanol was heated to 55° C. and adjusted to pH 4.5 using 2 N sulphuric acid. An aqueous solution of 0.22 g (0.7 mmol) of sodium tungstate in 7 ml of water was then added. At 55° C., 10 mol of hydrogen peroxide were then added over the course of 1 h, and the mixture was then cooled to room temperature and filtered. The slightly beige filtration residue was washed using 2×30 ml of a mixture of water/isopropanol 2:1 and 2×30 ml of water and then dried under reduced pressure at room temperature. This gave 7.43 g of the title product in a yield of 75%. ¹H-NMR (CDCl₃): 9.15 (1H, s); 8.18 (1H, d); 7.92 (2H, d); 7.47 (2H, d); 7.30 (1H, d); 4.39 (2H, s); 3.04 (3H, s); 2.63 (3H, s). 

1. Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone of the formula

characterized in that in the first, step a), 4-(methylthio)benzyl alcohol is converted with hydrochloric acid into 4-(methylthio)benzyl chloride, in the second step b), 4-(methylthio)benzyl chloride is converted with an alkali metal cyanide into 4-(methylthio)phenylacetonitrile, in the third step c), 4-(methylthio)phenylacetonitrile is condensed with a 6-methylnicotinic ester to give 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine of the formula

in the fourth step d), 3-[-(4-(methylthio)phenyl)-2-cyanoacetyl] (6-methyl)pyridine is hydrolysed and decarboxylated under acidic conditions to give 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine of the formula

and, in the last step e), 3-[2-(4-(methylthio)phenyl)acetyl] (6-methyl)pyridine is oxidized to give the end product.
 2. Process according to Patent claim 1, characterized in that the reaction in step a) is carried out at a temperature of from 10° C. to 40° C. and in an organic solvent.
 3. Process according to Patent claim 1 or 2, characterized in that the reaction in step b) is carried out in the presence of a phase transfer catalyst.
 4. Process according to any of Patent claims 1 to 3, characterized in that the reaction in step b) is carried out at a temperature of from 60° C. to 100° C.
 5. Process according to any of Patient claims 1 to 4, characterized in that the condensation in step c) is carried out in the presence of an alkali metal alkoxide at a temperature between 60° C. and 110° C.
 6. Process according to any of Patent claims 1 to 5, characterized in that the hydrolysis and decarboxylation in step d) is carried out using a mixture of acetic acid and a mineral acid, at a temperature of from 50° C. to 115° C.
 7. Process according to any of Patent claims 1 to 6, characterized in that the oxidation in step e) is carried out using hydrogen peroxide in the presence of an alkali metal tungstate, at a temperature of from 10° C. to 40° C. 